Humanin, MOTS-c and SS-31: mitochondrial peptides explained

Published 4 November 2026

Mitochondria, the energy-producing compartments of our cells, carry their own small piece of DNA. For decades it was thought to encode only 37 genes, all for energy production. Since 2001, researchers have found that it also hides very short genes for signalling peptides, now called mitochondrial-derived peptides. Humanin and MOTS-c are the two best studied. SS-31 is often mentioned alongside them, but it is a different kind of molecule: a synthetic peptide designed to reach mitochondria from outside. This guide explains all three.

At a glance

What "mitochondrial-derived peptides" are

The genes for Humanin and MOTS-c are tiny open reading frames that sit inside the mitochondrial genes for ribosomal RNA. Their discovery suggested that mitochondria do not only produce energy but also send signals to the rest of the cell and, through the blood, to other tissues. Both peptides circulate in blood, and in several studies their levels fall with age, which is one reason they are studied in ageing research.

Humanin

Humanin was discovered in 2001 by a Japanese group searching for genes that protected brain cells in Alzheimer's disease. Its gene came from a part of the brain that had been spared by the disease. In cell cultures, Humanin blocked nerve-cell death caused by several Alzheimer's-linked gene mutations and by amyloid-β.

Later work found that it acts both outside cells, through receptors on the cell surface, and inside them, by interfering with proteins that trigger programmed cell death. In animal studies it has been examined for protection of the brain, the heart and insulin-producing cells. A more potent variant with one amino-acid change, often called HNG, is used in much of the research.

All evidence for protective effects comes from cell and animal studies. No clinical trial of Humanin as a treatment has been published.

MOTS-c

MOTS-c was described in 2015 by a group at the University of Southern California. In mice, it targeted skeletal muscle, activated AMPK, the cell's energy sensor, and prevented both diet-induced obesity and the insulin resistance that develops with age or a high-fat diet.

A 2021 study found that exercise raises MOTS-c levels in muscle and blood in humans, and that giving MOTS-c to mice improved physical capacity at all ages, including late life. This is why it is often described as "exercise-mimetic" research.

The only human testing so far was of CB4211, a modified MOTS-c analogue. In a small four-week trial in people with obesity and fatty liver, the developer reported lower liver enzymes than placebo but no clear difference in liver fat or body weight. These were company-announced early results and have not been followed by larger trials.

SS-31

SS-31 is a synthetic tetrapeptide, not a natural mitochondrial product. It carries alternating positive charges and aromatic amino acids that let it cross cell membranes and concentrate on the inner mitochondrial membrane, where it binds cardiolipin, a fat that holds the energy-producing machinery together. The aim is to stabilise that membrane and reduce damage under stress.

Under the name elamipretide, it is the most advanced of the three in humans. In September 2025 the US FDA granted it accelerated approval for Barth syndrome, a rare inherited mitochondrial disease, based on improved muscle strength in a randomised trial; a confirmatory trial is required. It is not approved in the EU.

How they compare

• Natural vs synthetic: Humanin and MOTS-c are made by our own cells; SS-31 is a designed drug-like peptide.
• Signal vs repair: Humanin and MOTS-c act mainly as signals between cells and tissues; SS-31 acts directly on the mitochondrial membrane.
• Evidence level: SS-31 has controlled human trial data and an approval for one rare disease; MOTS-c has one small analogue trial; Humanin has none.

Regulatory status

Humanin and MOTS-c are not approved as medicines anywhere. Elamipretide is approved only in the US, only for Barth syndrome. The products we sell are supplied for laboratory research only.

Handling

All three are supplied as lyophilised powder. Keep unopened vials in the freezer and reconstituted solutions in the refrigerator. See our storage guide. For another compound studied in mitochondrial and metabolic research, see NAD+.

References

1. Hashimoto Y et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ. Proc Natl Acad Sci USA 2001;98(11):6336–6341.
2. Lee C, Yen K, Cohen P. Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab 2013;24(5):222–228.
3. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015;21(3):443–454.
4. Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021;12:470.
5. CohBar Inc. Topline results from the phase 1a/1b study of CB4211 (company announcement, August 2021).
6. US Food and Drug Administration. FDA grants accelerated approval to first treatment for Barth syndrome (elamipretide), September 2025.

For laboratory research use only. This guide summarises published research and is not medical advice. Our products are not for human consumption.